BACKGROUND:TB APPRISE (IMPAACT P1078), a Phase IV randomized, multi-country non-inferiority trial assessing the safety of 28 weeks of isoniazid preventive therapy (IPT) initiated during pregnancy (immediate IPT) versus deferring to week 12 postpartum (deferred IPT) in people with HIV on antiretroviral therapy, showed higher than expected hepatotoxicity. We investigated the potential roles of antiretrovirals, isoniazid, pharmacogenetics and other factors. METHODS:Hepatotoxicity was defined as Grade ≥3 liver enzyme elevations; or Grade ≥2 enzyme elevations with elevated bilirubin or symptomatic hepatitis. We performed Poisson regression of all-cause hepatotoxicity on study arm, antiretroviral regimen, pharmacogenetics of isoniazid and efavirenz metabolism (NAT2, CYP2B6) and other participant characteristics. Adjusted models included study arm and covariates with P < .25 in unadjusted models. Antiretroviral regimen and pharmacogenetics interactions with study arm were evaluated. RESULTS:All 945 pregnant participants with follow-up liver function measurements were on antiretrovirals (85% with efavirenz, 13% with nevirapine); 63 (6%) experienced hepatotoxicity events; 29 (6%) in immediate, and 34 (7%) in deferred arm; only 5 events (8%) occurred in pregnancy; 49 (78%) occurred between delivery and 24 weeks postpartum. Higher risk of hepatotoxicity was observed with nevirapine use in the immediate arm, but there was no difference by study arm in participants on efavirenz. Slow efavirenz metabolizers had increased risk of hepatotoxicity. CONCLUSIONS:It is critical to monitor for hepatotoxicity in early postpartum, where there is higher risk compared to antepartum. ARV regimen and pharmacogenetics should also be considered in making decisions on when to initiate IPT in pregnant and postpartum populations.

Understanding host susceptibility to Mycobacterium tuberculosis ( Mtb) is critical for the development of new vaccines. Certain individuals "resist" becoming infected with Mtb despite intensive exposure; however, it is unknown whether there is a genetic basis for "resistance" to Mtb infection across populations. Here we conducted a genome-wide association study (GWAS) of resistance to Mtb infection by carefully characterizing exposure to TB patients among 4,058 close contacts in India, Brazil, and South Africa. 476 (12%) "resisters" remained free of Mtb infection despite substantial exposure to highly infectious TB patients. GWAS identified a novel chromosome 13 locus (rs1295104126) associated with resistance across the multi-ancestry meta-analysis. Comparing Mtb -infection to all uninfected contacts, irrespective of exposure, yielded a different locus on chromosome 6 (rs28752534), near the HLA-II region. These findings demonstrate a common genetic basis for resistance to Mtb infection across multi-ancestral cohorts with potential to elucidate novel mechanisms of protection from Mtb infection.

BACKGROUND:Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of death from a single infectious agent worldwide. Exposure to Mtb results in diverse outcomes: bacterial clearance, latent infection, asymptomatic, or symptomatic TB. Current diagnostic tools cannot reliably distinguish these outcomes. Our previous studies identified Mtb proteins in extracellular vesicles (EVs) from TB patients' serum, suggesting their potential as biomarkers. Here, we aimed to discover Mtb proteins and peptides in serum EVs across TB stages, focusing on asymptomatic individuals. METHODS:Serum was obtained from healthy, HIV-negative South African adult volunteers enrolled in a TB risk study. Based on patients' outcomes, samples were classified as prevalent, incident (controls that progressed to TB), activated TB, or community controls. EVs were isolated using ExoQuick™, followed by protein digestion and mass spectrometry (MS) analysis. Data-independent acquisition (DIA) with five different data analysis strategies, and two data-dependent (DDA) methods were used to identify Mtb proteins. RESULTS:Our DIA analysis using ion-mobility and spectral libraries enriched with Mtb-MS data revealed 19 Mtb proteins. Rv2997 was significantly higher at baseline in individuals who were initially TB-negative (incident) but later became bacteriologically positive, asymptomatic-TB (activated). HspX, GroEL2, and GroES, together with a MtrB peptide were significantly different between controls and asymptomatic-TB cases. DDA approaches did not resolve additional Mtb proteins. CONCLUSIONS:Quantitative DIA analysis discovered Mtb proteins/peptides in serum-derived EVs that were differentially abundant in individuals with early, asymptomatic TB. These findings highlight their potential as biomarkers and provide insight into host-pathogen interactions during subclinical infection.

BACKGROUND:Diagnostic performance of tongue swab Mycobacterium tuberculosis PCR has been evaluated for facility-based triage of symptomatic tuberculosis (TB). It is unknown whether tongue swab performance differs for detection of asymptomatic TB in community-based screening. METHODS:Tongue swabs were collected from adult household contacts of TB patients (HHC Cohort), and symptomatic adults presenting to clinics with presumptive TB (Clinic Cohort), at eight South African sites. TB Cases were defined by positive sputum Xpert Ultra or liquid culture, performed in all participants; and matched ~1:3 (HHC Cohort) or ~1:2 (Clinic Cohort) to Controls without TB. Tongue swabs in both cohorts were tested by high-volume qPCR; and in the Clinic Cohort, also by sequence-specific magnetic capture (SSMaC) with qPCR. RESULTS:The Clinic Cohort included 217 TB Cases (100% symptomatic) and 437 Controls. The HHC Cohort included 44 TB Cases (84.1% asymptomatic) and 136 Controls. In the Clinic Cohort, sensitivity of SSMaC with qPCR was 73.2% (specificity 94.6%), but not significantly higher than high-volume qPCR (63.8%; p = 0.14) (specificity 94.4%). Sensitivity of high-volume qPCR in the Clinic Cohort (63.8%) was significantly higher than the HHC Cohort (34.1%; p = 0.0007) (specificity 91.9%). Among HHC, high-volume qPCR sensitivity was 35.1% for asymptomatic TB; 52.2% for TB with abnormal CXR; and 100% for TB with High sputum Xpert Ultra grade. CONCLUSIONS:Sensitivity of tongue swab high-volume qPCR for community-based, household screening for asymptomatic TB was low, approximately half that of facility-based triage for symptomatic TB, but increased with radiographic severity and sputum bacillary load.

Background Tuberculosis preventive therapy (TPT) is critical in interrupting progression to disease, transmission and reducing incidence rates. Nonetheless, high costs have been barriers towards the expansion of shorter patient-friendly drug regimens. In 2019, a Unitaid-led deal reduced rifapentine costs by over 70%, facilitating Brazil’s implementation of 3 months of rifapentine+isoniazid (3HP), a short-course TPT regimen, in its public health system. We evaluated the health and economic impact of Brazil’s implementation of this patient-friendly regimen for short-course TPT.Methods We analysed surveillance data on 171 174 individuals initiating TPT from January 2019 to December 2024. A mixed-effects spatiotemporal Bayesian model estimated quarterly TPT initiation trends under (1) observed 3HP rollout versus a no-3HP counterfactual (Q3 2021–Q4 2024) and (2) projected universal 3HP coverage (Q1 2025–Q4 2027) versus extended no-3HP adoption. Cost-effectiveness analysis quantified active tuberculosis (TB) cases and disability-adjusted life-years (DALYs) averted, alongside costs, incremental cost-effectiveness ratios, net monetary benefits (NMBs) and return on investment of TPT under each 3HP coverage scenario.Results From 2022 to 2024, 3HP scale-up produced 37 508.4 (95% credible intervals (CrIs) 31 405.2 to 43 631.6) additional TPT initiations, averted an estimated 15 002 DALYs (95% CrI 8985.6 to 21 031.15) and yielded NMBs of US$122.7 million (95% CrI US$63.8 to US$198.2 million). Under a proposed universal coverage (2025–2027), projected gains included 72 080.1 (95% CrI 62 323.7 to 81 836.4) additional individuals starting TPT, with subsequent 26 139 DALYs averted (95% CrI 14 117 to 38 762) and NMBs of US$214.5 million (95% CrI US$103.0 to US$362.8 million), indicating strong economic dominance over no-3HP adoption. Finally, TPT with 3HP’s implementation was estimated to return US$1.31 (95% CrI US$0.97 to US$1.62) to the health system for every US$1 invested.Conclusions In Brazil, large-scale implementation of a patient-friendly short-course regimen (3HP) was effective and likely cost-saving for a resource-strained public health system. Our evaluation provides robust, real-world evidence that implementing this regimen improved TPT coverage and completion nationwide while reducing costs and TB disease burden.

BACKGROUND:Stagnating decreases in Kaposi sarcoma (KS) among men with HIV (MWH) following Treat-All policies necessitate evaluating changes in clinical drivers of KS. We examined clinical factors and their associations with KS rates among MWH in North America. METHODS:Among MWH in the North American AIDS Cohort Collaboration on Research and Design, we estimated annual KS rates (per 100 000 person-years [PY]) by viral suppression (<200 copies/mL), CD4 count (<500 vs ≥500 cells/mm3), and time since ART initiation (<1 year/naive vs ≥1 year) from 2009-2019. We quantified associations between clinical factors and KS rates using negative binomial regression, estimating incidence rate ratios (IRRs) with 95% CIs. Among MWH with KS, we estimated average annual percentage changes (AAPCs) in clinical factor distribution using joinpoint regression. RESULTS:There were 61 155 MWH (370 624 PY) contributing 262 KS diagnoses. KS decreased from 132 to 43 cases per 100 000 PY between 2009 and 2019. Viral suppression (IRR2009: .09 [95% CI: .04-.20]; IRR2019: .69 [.31-1.54]), recent/no ART initiation (IRR2009: .14 [.07-.30]; IRR2019: 1.16 [.53, 2.56]), and CD4 count ≥500 cells/mm3 (IRR2009: .13 [.05-.31]; IRR2019: .44 [.18-1.10]) were associated with reduced KS rates, attenuating over time. Unsuppressed viral load at KS diagnosis decreased by 10.6% (-15.8%, -4.8%) as did those on ART ≤1 year/naive (70%-40%; AAPC: -6.3% [-13.8%, 2.1%]). CONCLUSIONS:Our findings underscore the importance of early HIV diagnosis/treatment in reducing KS burden. Attenuating associations with HIV factors indicate that those successfully managing HIV increasingly represent KS patients. KS drivers are evolving, requiring patient/population-level monitoring.

BACKGROUND:Approximately 95% of people infected with Mycobacterium tuberculosis do not progress to tuberculosis (TB) disease. Identifying key determinants of TB progression could focus prevention efforts. METHODS:Contacts of pulmonary TB patients were enrolled in a prospective multi-center cohort study (Regional Prospective Observational Research in Tuberculosis [RePORT]-Brazil) from 2015 to 2019 and followed for 24 months. Empirical review and least absolute shrinkage and selection operator (LASSO) regression, using baseline clinical and laboratory information, were used as dimension reduction techniques to determine factors for inclusion in prediction models. Models were created for: (1) all contacts, (2) contacts interferon-gamma release assay (IGRA)-positive at baseline, and (3) IGRA-positive contacts who did not receive TB preventive therapy (TPT; <30 days isoniazid). Internal validation was performed using bootstrapping. RESULTS:Among 1846 contacts of 619 TB index patients, 25 (1.4%) progressed to TB. No TPT was a risk factor for progression to TB among all contacts (mixed-effects adjusted hazard ratio [aHR] = 16.55, 95% confidence interval [CI]: 2.22-124.45). Internal validation with all contacts yielded an area under the receiver operating characteristic curve of 0.80 (95% CI: .72-.86]. Body mass index (BMI) was inversely associated with increased risk of progressing to active TB among IGRA-positive contacts who did not receive TPT (aHR = 0.89, 95% CI: .80-.99). Interferon-gamma release assay-positive contacts with BMI <25 kg/m2 had a 4.14-fold (95% CI: 1.17-14.67) higher risk of progression to TB than IGRA-positive contacts with BMI ≥25 kg/m2: 8.4% versus 2.1%, respectively. CONCLUSIONS:Body mass index <25 kg/m2, a readily available biomarker, identified IGRA-positive close TB contacts at high risk of progressing to TB disease. Prioritizing this high-risk group for TB preventive therapy could improve TB prevention efforts. BMI <25 kg/m², a readily available biomarker, identified IGRA-positive close contacts at high risk for progression to TB in a large observational Brazilian cohort. Prioritizing this high-risk group for TB preventive therapy could significantly improve TB prevention efforts.

Abstract Background Without tuberculosis preventive therapy (TPT), approximately 5% of individuals infected with M. tuberculosis progress to active tuberculosis (TB) disease. Recent studies have identified body mass index (BMI) < 25 kg/m 2 as a predictor of TB progression, but additional markers are needed to better identify persons at increased risk. Methods Close contacts of patients with culture-confirmed pulmonary TB were enrolled in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort from 2015 to 2019 and followed for up to 24 months. Analyses were restricted to interferon-γ release assay (IGRA)-positive contacts who did not receive TPT or received <30 days of isoniazid. Prediction models to identify close contacts at increased TB risk were constructed using two complementary approaches: incremental models used BMI as the base predictor and evaluated whether baseline whole-blood transcriptomic signatures, human genetic polymorphism risk scores derived from low-pass whole-genome sequencing, and BMI-related plasma biomarkers improved model discrimination. Agnostic models did not impose BMI in the model and used penalized regression for predictor selection. Results Among 285 close contacts, 15 (5%) progressed to TB. The model with BMI as unique predictor had a C-index of 0.66 (95% confidence interval [CI] 0.55; 0.77). Adding Rajan5 or Duffy9 transcriptomic signature scores to BMI improved discrimination compared with BMI alone, with C-indices of 0.78 (95% CI 0.62; 0.99) and 0.75 (95% CI 0.61; 0.89), respectively, but did not further improve discrimination after accounting for adiponectin. Adding adiponectin to BMI increased the C-index to 0.80 (95% CI 0.68; 0.91), while adiponectin alone captured most of the discriminatory performance in agnostic models (C-index, 0.80, 95% CI 0.69; 0.91). Genetic risk scores, leptin, and the adiponectin:leptin ratio did not improve model discrimination compared with the BMI-only model. In exploratory post hoc analyses, higher adiponectin was associated with increased risk of progression to TB, with each two-fold increase associated with a higher hazard of TB (HR 2.91, 95% CI 1.73; 4.91, p < 0.001). Conclusions Baseline adiponectin strongly predicted progression to TB among close contacts and captured most of the discriminatory information contained in epidemiological and transcriptomic variables. Its consistent selection across modelling approaches supports adiponectin as a promising biomarker for TB risk stratification.

BACKGROUND:Integrase strand transfer inhibitor (INSTI) initiation has been associated with diabetes in antiretroviral therapy (ART)-naive people with HIV. We aimed to examine the effect of switching to INSTIs on incident diabetes in ART-experienced people with HIV. METHODS:In this target trial emulation, we retrospectively used individual-level data from 27 longitudinal cohorts of people with HIV in the USA and Canada. We included participants aged at least 18 years without diabetes who had used non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors for at least 180 days (in 2016-22) but had never used an INSTI. We used data from any clinical encounters in which participants continued an NNRTI or protease inhibitor versus switched to an INSTI, with a follow-up period of up to 5 years. The effect of switching to INSTIs on incident diabetes was estimated with weighted Cox regression with robust variance. We further assessed whether the effect varied by time since the switch and was explained by weight gain in the first year. FINDINGS:13 071 participants were followed up from 2702 encounters in which they switched to an INSTI from an NNRTI, 54 766 encounters in which they continued an NNRTI, 1714 encounters in which they switched to an INSTI from a protease inhibitor, and 26 599 encounters in which they continued a protease inhibitor. Switching from protease inhibitors to INSTIs conferred an adjusted hazard ratio (HR) of 1·38 (95% CI 1·06-1·80) for incident diabetes, whereas switching from NNRTIs to INSTIs conferred an adjusted HR of 1·10 (0·87-1·39). The diabetes risk was higher during the first 2 years after switching from protease inhibitors to INSTIs (HR 1·67, 95% CI 1·21-2·30), but not thereafter (1·08, 0·75-1·57; pinteraction=0·064). The effect of switching from protease inhibitors to INSTIs on diabetes did not appear to be explained by weight gain. In the sensitivity analysis in which weight gain did not exceed 5% in the first year after, the switch from NNRTIs to INSTIs had a HR of 1·03 (95% CI 0·79-1·36) and the switch from protease inhibitors to INSTIs had a HR of 1·37 (1·02-1·84). INTERPRETATION:The increased diabetes risk after switching from protease inhibitors to INSTIs highlights a metabolic implication of regimen change and could warrant close monitoring early after switch, regardless of weight gain. FUNDING:US National Institutes of Health.

Background:High-risk subgroups among household contacts of persons with tuberculosis (TB) might benefit from additional interventions. However, the significance of an abnormal baseline chest radiograph (CXR) suggestive of TB, despite negative sputum microbiology, is uncertain. Methods:Adults (≥18 years) with recent household TB exposure were enrolled at three South African sites (April 2021-September 2022). All participants underwent symptom screening, CXR, and sputum Xpert Ultra and MGIT culture. Pulmonary TB diagnosis was microbiologically-confirmed. Participants were followed for symptomatic incident TB through 12 months. Multivariable logistic regression identified factors associated with abnormal CXR suggestive of TB. Poisson regression estimated incidence rate ratios (IRR). Results:Baseline CXR were abnormal in 157/795 (19.7%) participants; associated with older age (adjusted odds ratio, aOR=1.04, 95%CI 1.02-1.05); prior TB (aOR=6.39, 95%CI 4.18-9.78); and current smoking (aOR=1.61, 95%CI 1.00-2.62). Symptomatic incident TB developed in 8/795 (1.0%) participants, including 7/8 (87.5%) who were asymptomatic and 4/8 (50.0%) with abnormal CXR at baseline. TB incidence was four-fold higher in those with abnormal versus normal CXR (IRR=4.02, 95%CI 1.01-15.97), with a risk difference of 1,969 (95%CI -657-4,595) per 100,000 person-years, but after median 12.1 (IQR 11.1-13.1) months follow-up, 153/157 (97.5%) had not progressed to incident TB. Conclusions:Adult contacts with CXR abnormalities, but without prevalent TB, had a four-fold higher risk of TB within one year, compared to those with normal CXR. This additional risk warrants targeted preventive treatment and extended surveillance, but since most remained TB-free, therapeutic TB treatment is not justified.

Background:The World Health Organisation (WHO) recommends digital chest radiography (dCXR) with computer-aided detection (CAD) for tuberculosis (TB) screening of individuals >15 years of age. Methodology:Adults (≥18 years) were enrolled (March 2021-December 2022) in South Africa into a community-based Screening Cohort (household contacts) and a facility-based Triage Cohort (symptomatic clinic attendees). Microbiologically-confirmed pulmonary TB required positive sputum culture and/or Xpert Ultra. Asymptomatic TB was diagnosed in participants without TB symptoms. dCXR were read by blinded human readers and qXR CAD (0.5 threshold; Qure.AI, India). Results:dCXR from 1,353 participants (886 Screening Cohort; 467 Triage Cohort) were analysed. Microbiologically-confirmed TB occurred in 48 (5.4%) Screening Cohort [9 symptomatic (19%) and 39 asymptomatic (81%)]; and 116 (24.8%) Triage Cohort (all symptomatic) participants. dCXR sensitivity (human readers) for asymptomatic TB in the Screening Cohort was 56.4%, vs. 72.4% for symptomatic TB in the Triage Cohort (difference -16%; 95%CI -2.9 to -29.1); with specificities 94.1% and 81.2%, respectively. Corresponding qXR CAD sensitivities were 69.2% vs. 83.6% (difference -14.4%; 95%CI -26 to -2.8), with specificities 89.3% and 73.5%, respectively. The difference in dCXR sensitivity and specificity for asymptomatic TB between qXR CAD and human readers was 12.8% (95%CI -0.48 to 26.1) and -4.8% (95%CI -12.4 to 28.2), respectively. Conclusion:Sensitivity of community-based dCXR screening for microbiologically-confirmed asymptomatic TB among household contacts was lower than for facility-based triage of symptomatic TB, but approached 70% with CAD. Neither human reader nor qXR CAD evaluation met WHO targets for a TB screening test (90% sensitivity; 80% specificity).

ABSTRACT Introduction Latin America is a key region in advancing efforts to end the HIV epidemic globally. Despite breakthroughs in HIV treatment and prevention in the last 20 years, as well as region‐wide improvements in health infrastructure and policies, there has been a 13% increase in new acquisitions in Latin America from 2010 to 2024. The Caribbean, Central and South America network for HIV epidemiology (CCASAnet), established in 2006, is one of seven regions in the International epidemiology Databases to Evaluate AIDS (IeDEA). CCASAnet contributes substantially to regional science and the development of national and region‐wide policies. Here, we describe data sources and operational methodologies employed by CCASAnet, as well as the current state of the cohort. Methods CCASAnet data are collected using standardized data elements, including demographic information, HIV disease history, laboratory data, antiretroviral regimens, co‐infections and comorbidities. Data collection has expanded to include prospective data such as substance use, antiretroviral therapy adherence, geriatric syndromes and tuberculosis treatment. All clinical sites retain ownership of their data, and CCASAnet data contribute as able to global IeDEA‐level projects. Robust data quality initiatives and statistical methods have strengthened the cohort. Results CCASAnet consists of nine clinics across seven countries (Argentina, Brazil, Chile, Haiti, Honduras, Mexico and Peru). Over 61,000 adults and children living with HIV have contributed observational data through December 2023. While CD4 at enrolment has remained largely unchanged, time to antiretroviral therapy initiation has decreased, retention in care has improved and the proportion with undetectable HIV RNA has dramatically increased. Co‐infections and AIDS‐defining malignancies remain a cause of morbidity and mortality, but non‐communicable diseases have also increased. Overall mortality trends in the region have improved over time, with some notable exceptions. Conclusions Underscoring the importance of maintaining longitudinal collaborations and data collection, CCASAnet remains the largest source of high‐quality data for HIV epidemiology in Latin America and serves as an important evidence base for informing global and regional policy and stakeholder decisions related to the HIV epidemic.

Abstract Background Observational studies typically use routinely collected (RC) data to investigate TB treatment outcomes, but these data may be error-prone. Using RC data together with validated data on a subsample, we explored the association of TB testing results with mortality and TB treatment outcomes in persons living with HIV (PLWH). Method We used RC data from two large HIV observational cohorts to evaluate the association of TB test result (positive/negative/unknown) at treatment start with death and the composite unfavorable outcome (treatment failure, loss-to-follow-up [LTFU], recurrence, or death) within 1.5 years of TB treatment start. We designed and implemented an optimal multi-wave validation study on a subsample of PLWH. We fitted logistic regression models using RC data only and combining them with the chart-validated data using a generalized raking approach, controlling for age, sex, body mass index (BMI), antiretroviral therapy, CD4 count, and region. Results RC data were extracted from 22,587 PLWH; 1122 were selected for validation, with 842 validated. We observed large discrepancies between validated and unvalidated data. We found that PLWH who started TB treatment with negative test results had higher odds of death compared to those who started treatment with a positive test: adjusted odds ratio (aOR)=1.22 (95% confidence interval [CI]=[1.03-1.45]) and aOR=3.94 (95% CI=[1.73-9.00]), using RC data only and RC plus validated data, respectively. Results for the composite outcome were inconclusive. Conclusion In PLWH treated for TB, bacteriological confirmation was associated with lower mortality. Data validation for observational research using RC clinical data care is needed.

[This corrects the article DOI: 10.1016/j.lana.2024.100963.].

Background: Exposure to first-line anti-tuberculosis (TB) drugs varies significantly between individuals and populations. We developed population pharmacokinetic (PopPK) models using observational data from persons receiving fixed-dose combination (FDC) to evaluate the association of HIV, DM, and toxicity with drug exposure. Methods: RePORT-Brazil participants with drug-susceptible, culture-confirmed pulmonary TB treated with rifampin, isoniazid, pyrazinamide, and ethambutol (FDC) were included. Samples were obtained at month 1 of TB treatment. Age, sex, weight, DM- (according to glycated hemoglobin, non-DM ≤5·7%, pre-DM 5·8–6·4%, and DM ≥6·5%), HIV-status, and NAT2 profiles were examined. Adverse drug reactions (ADRs) were graded for severity. Liquid chromatography/Mass Spectrometry quantified drug concentration. Time since last dose was self-reported; samples >8h post-dose and with undetectable levels were excluded. Monolix® was used for model building and individual parameter estimation. AUC0-8 exposures were compared by DM-, HIV-status, and ADRs. Findings​: Of 388 unique samples (one per participant), 49 (13%) were excluded. Rifampin had the highest rate of undetectable levels (n=45, 13%), which was associated with shorter self-reported time between dose intake and sample collection (median 1·8 vs 3·0 hours, p<0·001) but not with other baseline characteristics. One-compartment PopPK models adequately described all drugs. AUC0-8 was lower among people with HIV (PWH) for rifampin (p=0·008) and ethambutol (p=0·022). Pre-DM and DM were associated with lower rifampin exposure (p=0·026 and p=0·004, respectively), and pre-DM with lower pyrazinamide exposure (p=0·027). PWH were more likely to experience grade ≥2 ADRs compared to HIV-negative individuals (30% vs 15%, p=0·003). Isoniazid exposure was higher among participants with grade ≥2 ADRs compared to those without (79·7 vs 73·5 mg·h/L, p=0·02). Interpretation: In people receiving TB treatment, four PopPK models demonstrated lower rifampin and ethambutol exposure among PWH, lower rifampin exposure with pre-DM and DM, lower pyrazinamide exposure with pre-DM, and higher isoniazid exposure among those with grade ≥2 ADRs. Funding: National Institutes of Health

BACKGROUND:Tuberculosis (TB) remains a leading infectious cause of death globally. While control strategies have traditionally prioritized symptomatic cases, growing evidence highlights the substantial burden of asymptomatic or subclinical TB, microbiologically confirmed disease without classical symptoms, posing challenges for detection, treatment, and elimination efforts. METHODS:We conducted a scoping review in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. We selected epidemiological studies, prevalence surveys, modeling analyses, and recent World Health Organization (WHO) guidance to summarize the current understanding of asymptomatic TB. We examined definitions, diagnostic approaches, transmission potential, natural history, and public health implications, with special focus on vulnerable populations. RESULTS:Prevalence surveys reveal that up to 30%-50% of bacteriologically confirmed TB cases may be asymptomatic at diagnosis, many of whom remain undetected under symptom-based screening. A substantial fraction of these individuals is smear positive, underscoring their potential role in community transmission. Despite clinical silence, radiographic and molecular studies demonstrate ongoing lung pathology and immune activation, with 20%-30% progressing to symptomatic disease within 2 years. Diagnostic challenges include low bacillary burden and inability to expectorate sputum, though innovations, such as computer-aided radiography, sputum pooling, and host transcriptomic biomarkers, are advancing detection. CONCLUSIONS:Asymptomatic TB represents a hidden but consequential component of the TB disease spectrum. Recognition and integration of this stage into TB control frameworks are essential for accurate burden estimation, timely treatment, and achievement of elimination targets. Future efforts must focus on scalable diagnostics, biomarker validation, and equitable screening strategies tailored to vulnerable populations.

Tuberculosis (TB) treatment is highly effective, but response to therapy varies by geography and population subgroups. We assessed differences in TB treatment response in a representative and heterogeneous Brazilian population. We estimated genetic ancestry according to major genetic ancestry groups (African, European, and Amerindian) in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort using ADMIXTURE software. RePORT-Brazil is an observational prospective cohort study of individuals with newly-diagnosed, culture-confirmed, pulmonary TB. Outcomes attributed to TB treatment included Grade 2 or higher adverse drug reaction (ADR), Grade 3 or higher ADR, hepatic ADR, and failure/recurrence. Genetic ancestry proportions were evaluated as predictors in univariate and multivariable logistic regression models for each outcome, and in stratified models for each genetic ancestry group. There were 930 pulmonary TB patients included in this study. In multivariable models we observed a decreased risk of Grade 2 + ADR when African ancestry proportion increased by 10

ABSTRACT Introduction Histoplasmosis remains a significant cause of morbidity and mortality in people with HIV . We examined disseminated histoplasmosis incidence, risk factors, and outcomes from North and South American HIV clinical sites. Methods Cohorts from Brazil, Chile, Honduras, Mexico, Peru and the United States (Tennessee) contributed data on PLWH ≥18 years old from 2000 to 2021. Stratifying by US and Latin American cohorts, we examined diagnosed disseminated histoplasmosis incidence and risk factors with modified Poisson regression models. Cox proportional hazard models examined factors associated with mortality after histoplasmosis. Results Of 26,672 people with HIV (Latin America n = 19,836; United States n = 6836), 214 had incident histoplasmosis(Latin America n = 140; United States n = 74). From 2000 to 2021, histoplasmosis incidence decreased from 16.08 to 0.93 in Latin America and 13.4 to 0.67 per 1000 person‐years in the United States. In Latin America, histoplasmosis risk was higher for males (aRR = 2.50 [95% CI: 1.62−3.86]), pre‐antiretroviral therapy initiation (aRR = 7.76 [95% CI: 5.05−11.90]) and those who had migrated from a histoplasma‐endemic country (aRR = 6.12 [95% CI: 1.81−20.69]). Risk was also higher for older people with HIV, those with low CD4, earlier calendar year and differed by site. In the United States, risk was higher in people with HIV with low CD4, higher HIV viral load, earlier calendar year and pre‐antiretroviral therapy initiation (aRR = 2.65 [95% CI: 1.11−6.36]). Mortality after histoplasmosis was higher in people with HIV with an earlier year of histoplasmosis 2000 versus 2010 (aHR = 2.00 [95% CI: 1.26−3.17]) and among those who developed histoplasmosis after antiretroviral therapy initiation compared to before antiretroviral therapy (aHR = 2.66 [95% CI: 1.43−4.95]). Conclusions Despite concern for underdiagnosis of disseminated histoplasmosis in Latin America, its incidence in people with HIV decreased, as it did in the United States. Low CD4 cell count and time before antiretroviral therapy initiation remain strongly associated with histoplasmosis risk. Further attention to early HIV diagnosis and treatment is needed.

RATIONALE:Non-sputum biomarkers to monitor tuberculosis treatment and predict poor outcomes are lacking. OBJECTIVES:To evaluate host-blood transcriptomic signatures for treatment monitoring and prognosis of death, treatment failure, and recurrence in adults with pulmonary tuberculosis. METHODS:Adults with culture-confirmed, drug-susceptible pulmonary tuberculosis were enrolled at 5 Brazilian sites. Whole-blood PAXgene samples were collected at baseline, month 2 (M2), and end of treatment (EoT). Treatment failure was defined as sputum culture positivity at month 5 or later. Participants were followed for 24 months from treatment initiation for clinical or microbiological tuberculosis recurrence. Unfavorable outcomes were matched ∼1:3 to recurrence-free cure. Twenty-two published blood transcriptomic signatures were measured by microfluidic RT-qPCR and benchmarked against the WHO Target Product Profile (TPP) criteria. MEASUREMENTS AND MAIN RESULTS:We matched 263 participants with recurrence-free cure to 33 with treatment failure, 24 who died (tuberculosis/unknown cause), and 9 with recurrence. Signature scores generally declined from baseline to EoT. Multiple signatures measured at baseline and M2 predicted recurrence (AUC range 0.71-0.91), with waning performance when measured at EoT (AUC range 0.42-0.89). Against the WHO TPP, 2/22 signatures met minimum criteria at baseline, 13/22 at M2, and none at EoT. Prediction of treatment failure was poor across timepoints (AUC < 0.70). In contrast, several signatures measured at baseline predicted death during treatment or follow-up (AUC ≥ 0.80). CONCLUSIONS:Blood transcriptomic signatures tracked treatment response and predicted recurrence and death, meeting WHO TPP benchmarks at baseline and M2. These findings support prospective, biomarker-guided trials to individualize tuberculosis therapy-shortening regimens for early responders and intensifying care for high-risk patients.

Background:Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are established antihypertensive treatments that reduce cardiovascular disease (CVD) risk. However, their comparative effectiveness in people with HIV (PWH) is not well examined. This study evaluated the comparative effectiveness of ACEIs and ARBs head-to-head and versus no antihypertensive treatment in preventing primary CVD. Methods:Using a target trial emulation framework and data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), we estimated observational analogs of intention-to-treat (ITT) and per-protocol (PP) effects of antihypertensive treatments in preventing primary CVD (myocardial infarction, non-MI coronary artery disease, stroke, transient ischemic attack, peripheral vascular disease, cardiovascular death) among hypertensive PWH, with subgroup analyses for Black and White PWH. Results:Compared with no antihypertensive treatment, ACEIs and ARBs were both associated with lower CVD risk in PWH, with similar effect sizes in ITT and PP analyses (ACEI ITT adjusted hazard ratio (HR): 0.79, 95% CI [0.70-0.89]; ACEI PP: 0.71 [0.55-0.90]; ARB ITT: 0.87 [0.65-1.16]; ARB PP: 0.37 [0.18-0.76]). Race-stratified ITT and PP analyses suggested somewhat greater risk reductions in White than Black PWH, although differences were not statistically significant. In head-to-head comparisons, ACEIs and ARBs showed comparable effectiveness overall (ITT: 1.14 [0.84-1.55]; PP: 0.54 [0.25-1.18]), and within race strata. Conclusions:Our study found that both ACEIs and ARBs were effective in reducing CVD risk among PWH, with similar effectiveness observed for both medications. The analysis did not reveal statistically significant differences in effectiveness between Black and White PWH for either drug.